Trk A, B, and C are commonly expressed in human astrocytes and astrocytic gliomas but not by human oligodendrocytes and oligodendroglioma

Abstract

Neurotrophins regulate the proliferation and differentiation of neurons in the central nervous system via a family of specialized receptors, including TrkA, TrkB, and TrkC. As little is known about their expression or potential role in human glial tissues and glial tumors, we undertook an immunohistochemical analysis of human glia, glioma tissues and cell cultures of glial tumors to characterize the expression of Trk family members (full-length TrkA, TrkB, the truncated form of TrkB, and TrkC). In normal human brain Trk A, B, and C immunoreactivity was found in neurons and some weak staining was also seen astrocytes. No Trk expression was seen on oligodendrocytes. Strong reactivity was seen in reactive astrocytes in a glial scar. In a total of 34 glioma tissue specimens, which included 16 astrocytic tumors (4 low-grade astrocytomas and 12 glioblastomas multiforme) and 15 oligodendrogliomas (8 low-grade and 7 anaplastic) as well as 3 oligoastrocytomas (WHO grade II), TrkA, B, and C immunoreactivity was observed exclusively in specimens from astrocytic gliomas (16/16), but not in any of the oligodendrocytic gliomas (0/15). In the oligoastrocytomas, staining was restricted to the astrocytic component. In the astrocytoma and oligodendroglioma specimens, Trk A, B, and C immunoreactivity was also seen in the surrounding reactive astrocytes. Trk expression was independent of age, sex or histological grade of the investigated tumors. In six primary cell cultures, one derived from human astrocytes and five established from malignant astrocytomas, only TrkA immunoreactivity could be detected, while TrkB (both full-length and truncated isoforms) and TrkC were absent. The TrkA expression in primary cell cultures decreased with continuous cell passaging, and no Trk could be detected in established cell lines derived from glioblastoma. In conclusion, our data suggest that in human glial tissues Trk A, B, and C may be expressed in a lineage-restricted manner, thereby distinguishing between astrocytes and oligodendrocytes in a marker-like fashion. Trk expression, like GFAP expression appears to be increased in activated (reactive)/neoplastic astrocytes.

Stimulation of the neurotrophin receptor TrkB on astrocytes drives nitric oxide production and neurodegeneration

“…We observed robust expression of TrkB on astrocytes in both EAE and MS lesions. Similarly, TrkB is enhanced in astrocytes in injured white matter (Frisén et al, 1993;Widenfalk et al, 2001) and after neoplastic transformation (Wang et al, 1998), suggesting a link between astrocyte activation and TrkB up-regulation. We demonstrated in our quantitative PCR experiments on human cerebral tissue that there was marked up-regulation of the truncated isoform TrkB-T1 in MS tissue compared with control white matter, which was confirmed at the protein level by immunohistochemistry with a specific antibody directed to the noncatalytically active isoform.…”

“…Astrocytes can express neurotrophin receptors (Wang et al, 1998), but the outcome of neurotrophin signaling in this cell type is still unclear. Astrocytes endow neurons with trophic and metabolic support and regulate dendritic growth and axon guidance (Blackburn et al, 2009).…”

TrkA immunoreactive astrocytes in dendritic fields of the hippocampal formation across estrous

“…Activated astrocytes appear within hours in the nervous system in response to diverse physical and chemical conditions (Althaus and Richter-Landsberg, 2000), increase TrkA expression (Wang et al, 1998), and can respond to neurotrophins in a receptor-mediated pathway (Grove et al, 1996). Interestingly, activated astrocytes also have been shown to express the TrkA ligand, NGF (Eddleston and Mucke, 1993;Althaus and Richter-Landsberg, 2000).…”

The antiapoptotic effect of guanosine is mediated by the activation of the PI 3‐kinase/AKT/PKB pathway in cultured rat astrocytes

“…Extracellular NGF, however, may play a role in the later stages of the antiapoptotic action of guanosine. As the protective effect of guanosine against staurosporine-induced death of astrocytes is detectable after 3 h of exposure, released NGF via Trk receptors (Condorelli et al, 1995;Wang et al, 1998;Climent et al, 2000) may activate the same cell survival pathways (PI3K/Akt/PKB and MAPK pathways) (Chao, 2003) and thus contribute to the overall protective action of guanosine.…”